bims-unfpre Biomed News
on Unfolded protein response
Issue of 2019–01–27
twelve papers selected by
Susan Logue, Apoptosis Research Centre
  1. IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.
  2. The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum.
  3. PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress.
  4. Application of Caenorhabditis elegans for Research on Endoplasmic Reticulum Stress.
  5. Endoplasmic reticulum stress: a key player in human disease.
  6. Small molecule ISRIB suppresses the integrated stress response within a defined window of activation.
  7. The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection.
  8. BET inhibitors potentiate chemotherapy and killing of SPOP-mutant colon cancer cells via induction of DR5.
  9. Reconstituting the reticular ER network - mechanistic implications and open questions.
  10. Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy.
  11. Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.
  12. Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis.
  1. Nat Commun. 2019 Jan 24. 10(1): 323
    IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.
    Xia Sheng, Hatice Zeynep Nenseth, Su Qu, Omer F Kuzu, Turid Frahnow, Lukas Simon, Stephanie Greene, Qingping Zeng, Ladan Fazli, Paul S Rennie, Ian G Mills, Håvard Danielsen, Fabian Theis, John B Patterson, Yang Jin, Fahri Saatcioglu.
      Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1α RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1α-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.
    DOI:  https://doi.org/10.1038/s41467-018-08152-3
  2. Cold Spring Harb Perspect Biol. 2019 Jan 22. pii: a033886. [Epub ahead of print]
    The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum.
    G Elif Karagöz, Diego Acosta-Alvear, Peter Walter.
      Most of the secreted and plasma membrane proteins are synthesized on membrane-bound ribosomes on the endoplasmic reticulum (ER). They require engagement of ER-resident chaperones and foldases that assist in their folding and maturation. Since protein homeostasis in the ER is crucial for cellular function, the protein-folding status in the organelle's lumen is continually surveyed by a network of signaling pathways, collectively called the unfolded protein response (UPR). Protein-folding imbalances, or "ER stress," are detected by highly conserved sensors that adjust the ER's protein-folding capacity according to the physiological needs of the cell. We review recent developments in the field that have provided new insights into the ER stress-sensing mechanisms used by UPR sensors and the mechanisms by which they integrate various cellular inputs to adjust the folding capacity of the organelle to accommodate to fluctuations in ER protein-folding demands.
    DOI:  https://doi.org/10.1101/cshperspect.a033886
  3. Sci Rep. 2019 Jan 23. 9(1): 410
    PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress.
    Isabelle C Romine, R Luke Wiseman.
      The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs secretion of destabilized TTR during thapsigargin (Tg)-induced ER stress by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition increases the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.
    DOI:  https://doi.org/10.1038/s41598-018-37207-0
  4. Prev Nutr Food Sci. 2018 Dec;23(4): 275-281
    Application of Caenorhabditis elegans for Research on Endoplasmic Reticulum Stress.
    Yuejia Xu, Yeonhwa Park.
      Caenorhabditis elegans is a versatile model organism that has been applied to research involving obesity, aging, and neurodegenerative diseases. C. elegans has many advantages over traditional animal models, including ease of handling, a short lifespan, a fully sequenced genome, ease of genetic manipulation, and a high similarity to human disease-related genes. With established C. elegans models of human disease, C. elegans provides a great platform for studying disease pathologies, including endoplasmic reticulum (ER) stress, which is characterized by the accumulation of unfolded and misfolded proteins involved in the pathologies of many diseases. ER stress can lead to activation of the unfolded and misfolded protein response, a mechanism that attenuates ER stress and recovers ER homeostasis. The current review gives an introduction to C. elegans and ER stress, along with the pathological role of ER stress in disease and the application of worm models in ER stress-related research.
    Keywords:  Caenorhabditis elegans; endoplasmic reticulum stress; unfolded protein response
    DOI:  https://doi.org/10.3746/pnf.2018.23.4.275
  5. FEBS J. 2019 Jan;286(2): 228-231
    Endoplasmic reticulum stress: a key player in human disease.
    Stefan J Marciniak.
      This Special Issue comprises eleven excellent reviews that illustrate the role of ER stress in different human diseases, including myopathies and lung diseases, as well as in modulating liver dysfunction and inflammatory responses. These reviews also highlight the function of the UPR in neurodegenerative disorders and cancer, while discussing the potential benefits of targeting the UPR as a therapeutic approach. We hope you find these reviews interesting and informative and we thank the authors for these excellent contributions.
    Keywords:  ER stress; disease; unfolded protein response
    DOI:  https://doi.org/10.1111/febs.14740
  6. Proc Natl Acad Sci U S A. 2019 Jan 23. pii: 201815767. [Epub ahead of print]
    Small molecule ISRIB suppresses the integrated stress response within a defined window of activation.
    Huib H Rabouw, Martijn A Langereis, Aditya A Anand, Linda J Visser, Raoul J de Groot, Peter Walter, Frank J M van Kuppeveld.
      Activation of the integrated stress response (ISR) by a variety of stresses triggers phosphorylation of the α-subunit of translation initiation factor eIF2. P-eIF2α inhibits eIF2B, the guanine nucleotide exchange factor that recycles inactive eIF2•GDP to active eIF2•GTP. eIF2 phosphorylation thereby represses translation. Persistent activation of the ISR has been linked to the development of several neurological disorders, and modulation of the ISR promises new therapeutic strategies. Recently, a small-molecule ISR inhibitor (ISRIB) was identified that rescues translation in the presence of P-eIF2α by facilitating the assembly of more active eIF2B. ISRIB enhances cognitive memory processes and has therapeutic effects in brain-injured mice without displaying overt side effects. While using ISRIB to investigate the ISR in picornavirus-infected cells, we observed that ISRIB rescued translation early in infection when P-eIF2α levels were low, but not late in infection when P-eIF2α levels were high. By treating cells with varying concentrations of poly(I:C) or arsenite to induce the ISR, we provide additional proof that ISRIB is unable to inhibit the ISR when intracellular P-eIF2α concentrations exceed a critical threshold level. Together, our data demonstrate that the effects of pharmacological activation of eIF2B are tuned by P-eIF2α concentration. Thus, ISRIB can mitigate undesirable outcomes of low-level ISR activation that may manifest neurological disease but leaves the cytoprotective effects of acute ISR activation intact. The insensitivity of cells to ISRIB during acute ISR may explain why ISRIB does not cause overt toxic side effects in vivo.
    Keywords:  ISRIB; P-eIF2; eIF2B; integrated stress response
    DOI:  https://doi.org/10.1073/pnas.1815767116
  7. Front Immunol. 2018 ;9 3083
    The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection.
    Hai Hu, Mingxing Tian, Chan Ding, Shengqing Yu.
      Apoptosis is a form of cell death by which the body maintains the homeostasis of the internal environment. Apoptosis is an initiative cell death process that is controlled by genes and is mainly divided into endogenous pathways (mitochondrial pathway), exogenous pathways (death receptor pathway), and apoptotic pathways induced by endoplasmic reticulum (ER) stress. The homeostasis imbalance in ER results in ER stress. Under specific conditions, ER stress can be beneficial to the body; however, if ER protein homeostasis is not restored, the prolonged activation of the unfolded protein response may initiate apoptotic cell death via the up-regulation of the C/EBP homologous protein (CHOP). CHOP plays an important role in ER stress-induced apoptosis and this review focuses on its multifunctional roles in that process, as well as its role in apoptosis during microbial infection. We summarize the upstream and downstream pathways of CHOP in ER stress induced apoptosis. We also focus on the newest discoveries in the functions of CHOP-induced apoptosis during microbial infection, including DNA and RNA viruses and some species of bacteria. Understanding how CHOP functions during microbial infection will assist with the development of antimicrobial therapies.
    Keywords:  C/EBP homologous protein; apoptosis; bacteria; endoplasmic reticulum stress; microorganisms; virus
    DOI:  https://doi.org/10.3389/fimmu.2018.03083
  8. Cancer Res. 2019 Jan 23. pii: canres.3223.2018. [Epub ahead of print]
    BET inhibitors potentiate chemotherapy and killing of SPOP-mutant colon cancer cells via induction of DR5.
    Xiao Tan, Jingshan Tong, Yi-Jun Wang, Rochelle Fletcher, Robert E Schoen, Jian Yu, Liangfang Shen, Lin Zhang.
      Bromodomain and extra-terminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that Death Receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer (CRC) cells. Induction of DR5 following BET inhibition was mediated by endoplasmic reticulum (ER) stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in CRC cells containing a mutation in Speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a CRC xenograft model, BETi combined with chemotherapy suppressed tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft (PDX) tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against CRC due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved CRC combination therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-18-3223
  9. J Cell Sci. 2019 Jan 22. pii: jcs227611. [Epub ahead of print]132(4):
    Reconstituting the reticular ER network - mechanistic implications and open questions.
    Ning Wang, Tom A Rapoport.
      The endoplasmic reticulum (ER) is a major membrane-bound organelle in all eukaryotic cells. This organelle comprises morphologically distinct domains, including the nuclear envelope and peripheral sheets and tubules. The tubules are connected by three-way junctions into a network. Several membrane proteins have been implicated in network formation; curvature-stabilizing proteins generate the tubules themselves, and membrane-anchored GTPases fuse tubules into a network. Recent experiments have shown that a tubular network can be formed with reconstituted proteoliposomes containing the yeast membrane-fusing GTPase Sey1 and a curvature-stabilizing protein of either the reticulon or REEP protein families. The network forms in the presence of GTP and is rapidly disassembled when GTP hydrolysis of Sey1 is inhibited, indicating that continuous membrane fusion is required for its maintenance. Atlastin, the ortholog of Sey1 in metazoans, forms a network on its own, serving both as a fusion and curvature-stabilizing protein. These results show that the reticular ER can be generated by a surprisingly small set of proteins, and represents an energy-dependent steady state between formation and disassembly. Models for the molecular mechanism by which curvature-stabilizing proteins cooperate with fusion GTPases to form a reticular network have been proposed, but many aspects remain speculative, including the function of additional proteins, such as the lunapark protein, and the mechanism by which the ER interacts with the cytoskeleton. How the nuclear envelope and peripheral ER sheets are formed remain major unresolved questions in the field. Here, we review reconstitution experiments with purified curvature-stabilizing proteins and fusion GTPases, discuss mechanistic implications and point out open questions.
    Keywords:  Atlastin; Cell biology; Endoplasmic reticulum; Lunapark; Reconstitution; Reticulon
    DOI:  https://doi.org/10.1242/jcs.227611
  10. FASEB J. 2019 Jan 22. fj201801983R
    Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy.
    Li Zhou, Wei Gao, Kui Wang, Zhao Huang, Lu Zhang, Zhe Zhang, Jing Zhou, Edouard C Nice, Canhua Huang.
      Colorectal cancer (CRC) is one of the most prevalent neoplastic diseases worldwide, and effective treatment remains a challenge. Here, we found that the macrolide antibiotic brefeldin A (BFA) exhibits considerable antitumor activity both in vitro and in vivo. Induction of complete autophagic flux is characterized as a key event in BFA-induced CRC suppression. Mechanistically, BFA provokes endoplasmic reticulum stress-mediated binding immunoglobulin protein (Bip) expression, leading to increased Bip/Akt interaction and resultant decreased Akt phosphorylation, thereby activating autophagy. Autophagy inhibition or Bip suppression relieves BFA-induced cell death, suggesting a key role for Bip-regulated autophagy in the antitumor properties of BFA. Moreover, BFA acts synergistically with paclitaxel or 5-fluorouracil in CRC suppression. Collectively, our study provides an important molecular basis for BFA-induced autophagy and suggests that the antibiotic BFA could be repositioned as a potential anticancer drug for CRC treatment.-Zhou, L., Gao, W., Wang, K., Huang, Z., Zhang, L., Zhang, Z., Zhou, J., Nice, E. C., Huang, C. Brefeldin A inhibits colorectal cancer growth by triggering Bip/Akt-regulated autophagy.
    Keywords:  ER stress; autophagic flux; cancer therapy
    DOI:  https://doi.org/10.1096/fj.201801983R
  11. Cold Spring Harb Perspect Biol. 2019 Jan 22. pii: a033928. [Epub ahead of print]
    Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases.
    Patrick G Needham, Christopher J Guerriero, Jeffrey L Brodsky.
      Misfolded proteins compromise cellular homeostasis. This is especially problematic in the endoplasmic reticulum (ER), which is a high-capacity protein-folding compartment and whose function requires stringent protein quality-control systems. Multiprotein complexes in the ER are able to identify, remove, ubiquitinate, and deliver misfolded proteins to the 26S proteasome for degradation in the cytosol, and these events are collectively termed ER-associated degradation, or ERAD. Several steps in the ERAD pathway are facilitated by molecular chaperone networks, and the importance of ERAD is highlighted by the fact that this pathway is linked to numerous protein conformational diseases. In this review, we discuss the factors that constitute the ERAD machinery and detail how each step in the pathway occurs. We then highlight the underlying pathophysiology of protein conformational diseases associated with ERAD.
    DOI:  https://doi.org/10.1101/cshperspect.a033928
  12. JCI Insight. 2019 Jan 24. pii: 124232. [Epub ahead of print]4(2):
    Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis.
    Sarrabeth Stone, Yuan Yue, Milos Stanojlovic, Shuangchan Wu, Gerard Karsenty, Wensheng Lin.
      Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating and neurodegenerative diseases of the CNS. Although neurodegeneration is the major contributor to chronic disability in MS, mechanisms governing the viability of axons and neurons in MS and EAE remain elusive. Data indicate that activation of pancreatic endoplasmic reticulum kinase (PERK) influences, positively or negatively, neuron and axon viability in various neurodegenerative diseases through induction of ATF4. In this study, we demonstrate that the PERK pathway was activated in neurons during EAE. We found that neuron-specific PERK inactivation impaired EAE resolution and exacerbated EAE-induced axon degeneration, neuron loss, and demyelination. Surprisingly, neuron-specific ATF4 inactivation did not alter EAE disease course or EAE-induced axon degeneration, neuron loss, and demyelination. These results suggest that PERK activation in neurons protects axons and neurons against inflammation in MS and EAE through ATF4-independent mechanisms.
    Keywords:  Multiple sclerosis; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.124232
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